According to the American Cancer Society an estimated 182,000 cases of invasive breast cancer occurred in the US in 2008, with 40,000 deaths due to breast cancer. Among women with metastatic breast cancer, the 5-year survival rate is 27%. The studies proposed in this SBIR phase I application are designed to assess the feasibility of developing synthetic schweinfurthins for the treatment of breast cancer. The first schweinfurthins from a family of natural products were isolated by workers at the National Cancer Institute and showed remarkable activity against the breast, leukemia/lymphoma, renal, melanoma and CNS sub-panels of the NCI 60-cell line bioassay. The schweinfurthins appear to have a novel mechanism of action and could have broad applicability to address the significant unmet medical need of patients with breast cancer. While initially discovered during a natural products screen, the natural sources of these compounds supply only small amounts and have proven unreliable for re-isolation. Terpenoid Therapeutics and its collaborators at the University of Iowa have designed and synthesized over fifty schweinfurthin analogues, including several compounds which have low nanomolar potency against human breast cancer cell lines in vitro. The goal of this phase I feasibility application is to establish in vivo efficacy of synthetic schweinfurthins in human breast cancer xenograft models. This project will undertake the further development of synthetic schweinfurthins for the treatment of breast cancer through two specific aims: 1) Analyze synthetic schweinfurthins alone and in combination with drugs currently used in the treatment of breast cancer for in vitro growth inhibition of human breast cancer cell lines and select compounds for testing in in vivo efficacy models;and 2) Test a synthetic schweinfurthin alone and in combination with standard therapies in breast cancer xenograft models to establish in vivo efficacy. The data from these studies will support a Phase II SBIR proposal to advance a synthetic schweinfurthin into IND-enabling studies. PUBLIC HEALTH RELEVANCE: In spite of important advances in the treatment of metastatic breast cancer, there remains a need for innovative new therapies. According to the American Cancer Society an estimated 182,000 cases of invasive breast cancer occurred in the US in 2008, with 40,000 deaths due to breast cancer. Among women with metastatic breast cancer, the 5-year survival rate is 27%. Research to identify novel treatments for metastatic breast cancer, such as the synthetic schweinfurthins, is needed to improve the outcomes for patients.